Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Cell Rep. 2021 May 18;35(7):109136. doi: 10.1016/j.celrep.2021.109136.
The cyclic AMP pathway promotes melanocyte differentiation by activating CREB and the cAMP-regulated transcription co-activators 1-3 (CRTC1-3). Differentiation is dysregulated in melanomas, although the contributions of CRTC proteins is unclear. We report a selective differentiation impairment in CRTC3 KO melanocytes and melanoma cells, due to downregulation of oculo-cutaneous albinism II (OCA2) and block of melanosome maturation. CRTC3 stimulates OCA2 expression by binding to CREB on a conserved enhancer, a regulatory site for pigmentation and melanoma risk. CRTC3 is uniquely activated by ERK1/2-mediated phosphorylation at Ser391 and by low levels of cAMP. Phosphorylation at Ser391 is constitutively elevated in human melanoma cells with hyperactivated ERK1/2 signaling; knockout of CRTC3 in this setting impairs anchorage-independent growth, migration, and invasiveness, whereas CRTC3 overexpression supports cell survival in response to the mitogen-activated protein kinase (MAPK) inhibitor vemurafenib. As melanomas expressing gain-of-function mutations in CRTC3 are associated with reduced survival, our results suggest that CRTC3 inhibition may provide therapeutic benefit in this setting.
环腺苷酸（cAMP）途径通过激活 CREB 和 cAMP 调节的转录共激活因子 1-3（CRTC1-3）来促进黑素细胞分化。尽管 CRTC 蛋白的作用尚不清楚，但黑色素瘤中的分化失调。我们报告了 CRTC3 KO 黑素细胞和黑色素瘤细胞中的选择性分化障碍，这是由于 oculo-cutaneous albinism II（OCA2）下调和黑素体成熟受阻所致。CRTC3 通过与 CREB 在保守增强子上结合来刺激 OCA2 的表达，该增强子是色素沉着和黑色素瘤风险的调节位点。CRTC3 通过 ERK1/2 介导的 Ser391 磷酸化和低水平的 cAMP 被独特激活。在 ERK1/2 信号过度激活的人类黑色素瘤细胞中，Ser391 的磷酸化持续升高；在这种情况下敲除 CRTC3 会损害锚定非依赖性生长、迁移和侵袭能力，而 CRTC3 的过表达则支持细胞在丝裂原激活的蛋白激酶（MAPK）抑制剂 vemurafenib 作用下的存活。由于表达 CRTC3 功能获得性突变的黑色素瘤与存活率降低相关，我们的结果表明，在这种情况下抑制 CRTC3 可能具有治疗益处。
